Morbidity and mortality secondary to cardiovascular disease is the major health problem in obese patients. Obese patients are burdened with an array of metabolic dysfunctions associated with excess weight which drive the cardiovascular disease evident in this population. While this correlation is well-established, mechanistic links that could be exploited therapeutically are largely lacking. In preliminary studies for this proposal, we have made two major observations that shed significant new light on this issue. The first is that loss of metabolic control in skeletal muscle appears to be the key trigger for vascular injury in obesity. Correction of rapid glucose disposal by deletion of genes that limit insulin signaling or muscle growth appear to restore endothelial function in vitro and may underpin cardiovascular defects systemically. The second observation is the NADPH Oxidase 1 (Nox1) is a major culprit in vascular defects in obesity. Nox1 is overexpressed in large and small vessels from obese mice and appears driven by glucose excess, potentially via upregulation of galectin-3. In the current proposal, we will rigorously test these concepts in three aims. The firs aim will use state-of-the-art molecular techniques in vitro to determine the signaling mechanisms by which changes in the plasma milieu, specifically glucose, induce changes in Nox expression and superoxide production with specific emphasis on the role of galectin-3. The second aim will generate novel Nox1 and Galectin-3 KO mice on a genetically obese background to test the hypothesis that these two oxidant pathways contribute to vascular dysfunction in vitro with a specific emphasis on determining whether improving metabolism by increasing muscle mass obviates pro oxidant pathways. The third aim will pursue these concepts in vivo, testing whether increased muscle mass or blocking the Nox1/Galectin-3 signaling axis improves cardiovascular outcomes like blood pressure and vascular adaptions to hemodynamic stress. Taken together, these studies will provide new information on the mechanisms, mediators and physiologic impact of obesity-induced metabolic dysfunction. Successful completion of these aims may identify new targets to aid in the treatment of some the most pressing clinical outcomes of obesity.